Polypyrimidine tract-binding protein regulates the cell cycle through IRES-dependent translation of CDK11p58 in mouse embryonic stem cells

Abstract

Polypyrimidine tract-binding protein (PTB/PTBP1/hnRNP I) is a member of the heterogeneous nuclear ribonucleoprotein family that binds specifically to pyrimidine-rich sequences of RNAs. Although PTB is a multifunctional protein involved in RNA processing and internal ribosome entry site (IRES)-dependent translation, the role of PTB in early mouse development is unclear. Ptb knockout mice exhibit embryonic lethality shortly after implantation and Ptb-/- embryonic stem (ES) cells have a severe proliferation defect that includes a prolonged G2/M phase. The present study shows that PTB promotes M phase progression by the direct repression of CDK11p58 IRES activity in ES cells. The protein expression and IRES activity of CDK11p58 in Ptb-/- ES cells is higher than that of wild-type ES cells, indicating that PTB is involved in the repression of CDK11p58 expression through IRES-dependent translation in ES cells. Interestingly, CDK11p58 IRES activity is activated by upstream of N-Ras (UNR) in 293T and NIH3T3 cells, whereas UNR is not present in the Cdk11 mRNA-protein complex in ES cells. In addition, PTB interacts directly with the IRES region of CDK11p58 in ES cells. These results suggest that PTB regulates the precise expression of CDK11p58 through direct interaction with CDK11p58 IRES and promotes M phase progression in ES cells.